The present invention relates to an improved process for producing chloropyrimidine compounds from hydroxypyrimidine compounds.
Chloropyrimidine compounds are valuable intermediates in the preparation of a wide variety of end use products, especially agricultural and pharmaceutical products. Such compounds, especially 2-, 4-, and 6-chloropyrimidine compounds, are typically prepared by the reaction of the corresponding hydroxypyrimidine compound with phosphorus oxychloride. The general process is described by D. J. Brown in "The Pyrimidines" from the monograph series "The Chemistry of Heterocyclic Compounds", pages 162-167 (1962) and many other well known publications. The process is sometimes carried out in the presence of a tertiary amine, which acts as an acid acceptor and a reaction promoter. The process as described in the art is, further, carried out in the presence of either a large excess of phosphorus oxychloride or of an organic solvent, such as acetonitrile or o-dichlorobenzene, which acts as a diluent to keep the reaction mixture fluid. The excess phosphorus oxychloride and/or organic solvent that is required increases the raw material cost of the chlorination process, makes expensive recycling of the diluent mandatory, and reduces the capacity of the production equipment.
In laboratory scale operations (for example, U.S. Pat. No. 5,057,517) and in the older art, the chloropyrimidine compounds produced by the reaction of an hydroxypyrimidine compound with phosphorus oxychloride are recovered by hydrolyzing the by-product chlorophosphoric acid compounds and excess phosphorus oxychloride with water and then removing the chloropyrimidine compound from the mixture obtained by filtration or extraction. A portion of the excess phosphorus oxychloride is sometimes removed by distillation before this operation. This procedure creates a large volume of undesirable aqueous phosphate waste. In recent years, the process for converting the by-product chlorophoshoric acids to phosphorus oxychloride by reaction with phosphorus pentachloride or with phosphorus trichloride and chlorine that is described, for example, in U.S. Pat. No. 3,845,194 has typically been used to reduce the cost and minimize the waste disposal problems. When this recovery process is employed, the phosphorus oxychloride reaction is generally carried out as described above and then, in a subsequent step, phosphorus pentachloride or phosphorus trichloride and chlorine are added. The phosphorus oxychloride produced in this manner and the excess used in the process are then separated from the mixture by distillation. A high boiling solvent, such as diphenyl ether, is sometimes added to facilitate the distillation. The desired chloropyrimidine compound is then recovered from the distillation residue by further distillation to recover the chloropyrimidine compound (EP 747364, published May 28, 1997), by filtration to remove the insoluble amine salts from the (liquid) chloropyrimidine compound either directly or after adding an organic solvent (U.S. Pat. No. 5,525,724), or by dilution with water followed by filtration, phase separation, or extraction with an organic solvent. The trialkylamine hydrochloride compound by-products formed as a result of these operations are typically recovered for recycle by basification. None of these recovery processes, however, is entirely satisfactory because of thermal decomposition, product losses and difficulties in the separations, and other yield reducing problems.